Cyclohexyl-1,4-diamine compounds

ABSTRACT

Novel cyclohexyl-1,4-diamine compounds corresponding to formula I  
                 
processes for preparing such compounds, pharmaceutical formulations comprising these compounds, methods of making such pharmaceutical formulations and the related methods of treating or inhibiting certain conditions or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International patent applicationSerial No. PCT/EP2005/004912 filed May 6, 2005 which claims benefit toGerman patent application Serial No. 10 2004 023 506.6 filed May 10,2004, the entire disclosures of which are hereby incorporated in theirentirety.

FIELD OF THE INVENTION

The present invention relates to cyclohexyl-1,4-diamine compounds,processes for preparing such compounds, pharmaceutical formulationscomprising these compounds, methods of making such pharmaceuticalformulations and the related methods of treating or inhibiting certainconditions or disorders.

BACKGROUND OF THE INVENTION

The treatment of chronic and non-chronic states of pain is of greatimportance in medicine. There is a worldwide need for pain therapieswhich are highly effective. The urgent need for action for targetedtreatment of chronic and non-chronic states of pain appropriate for thepatient, by which is to be understood successful and satisfactory paintreatment for the patient, is documented in the large number ofscientific works which have been published recently in the field ofapplied analgesics and of basic research into nociception.

Conventional μ-opioids, such as morphine, have a good action in thetherapy of severe to very severe pain and are of very great importancefor pain therapy. However, it may be of advantage if, in addition to theμ-opioid receptor, other opioid receptors, in particular the ORL1receptor, are influenced since pure μ-opioids also have undesirable sideeffects, such as constipation and respiratory depression, and can alsolead to dependency. The δ, κ and ORL1 opioid receptors are also involvedin the pain event (Opioids: Introduction, p. 127-150, Further OpioidReceptors, 455-476 in: Analgesics—From Chemistry and Pharmacology toClinical Application, Wiley VCH, 2002).

It is moreover known that influencing of the reuptake of serotoninand/or noradrenaline can have a favourable effect on the action spectrumand spectrum of side effects of opioids (example: tramadol, cf. Opioidswith Clinical Relevance: Tramadol, 228-230 in: Analgesics—From Chemistryand Pharmacology to Clinical Application, Wiley VCH 2002).

The ORL1 receptor is moreover also involved in regulation of furtherphysiological and pathophysiological processes. These include, interalia, learning and memory development (Manabe et al., Nature, 394, 1997,p. 577-581), audition (Nishi et al., EMBO J., 16, 1997, p. 1858-1864)and numerous further processes. A review article by Calo et al. (Br. J.Pharmacol., 129, 2000, 1261-1283) gives an overview of the indicationsor biological processes in which the ORL1 receptor plays a role or withhigh probability could play a role. There are mentioned, inter alia:analgesia, stimulation and regulation of food intake, influence onμ-agonists, such as morphine, treatment of withdrawal symptoms,reduction in the addiction potential of opioids, anxiolysis, modulationof movement activity, memory impairments, epilepsy; modulation ofneurotransmitter secretion, in particular of glutamate, serotonin anddopamine, and therefore neurodegenerative diseases; influencing of thecardiovascular system, initiation of an erection, diuresis,antinatriuresis, electrolyte balance, arterial blood pressure, waterretention diseases, intestinal motility (diarrhea), relaxing effects onthe respiratory tract, micturition reflex (urinary incontinence). Theuse of agonists and antagonists as anoretics, analgesics (also inco-administration with opioids) or nootropics is also discussed.

Structurally related compounds which have an affinity for the ORL1receptor are known from the prior art (WO 02090317). No influence on thereuptake of noradrenaline and serotonin has hitherto been described forthis structure class.

SUMMARY OF THE INVENTION

The object of the present invention was to provide medicaments which acton the opioid receptor system and are therefore suitable formedicaments, in particular for treatment of the various diseasesassociated with this system according to the prior art, and for use inthe indications mentioned there. The compounds should furthermoreinfluence the reuptake of noradrenaline and serotonin.

The invention therefore provides substituted cyclohexyl-1,4-diaminederivatives of the general formula I

wherein

-   -   R¹ and R² independently of one another represent H; C₁₋₅-alkyl,        in each case saturated or unsaturated, branched or unbranched,        mono- or polysubstituted or unsubstituted; C₃₋₈-cycloalkyl, in        each case mono- or polysubstituted or unsubstituted; or aryl,        C₃₋₈-cycloalkyl or heteroaryl bonded via C₁₋₃-alkyl and in each        case mono- or polysubstituted or unsubstituted;    -   or the radicals R¹ and R² together represent CH₂CH₂OCH₂CH₂,        CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆,    -   wherein R¹⁰ denotes H; C₁₋₅-alkyl, in each case saturated or        unsaturated, branched or unbranched, mono- or polysubstituted or        unsubstituted; C₃₋₈-cycloalkyl, in each case mono- or        polysubstituted or unsubstituted; aryl or heteroaryl, in each        case mono- or polysubstituted or unsubstituted; or aryl,        C₃₋₈-cycloalkyl or heteroaryl bonded via C₁₋₃-alkyl and in each        case mono- or polysubstituted or unsubstituted; C(O)phenyl,        C(O)heteroaryl, C(O)C₁₋₅-alkyl, in each case substituted or        unsubstituted;

R³ represents C₁₋₅-alkyl, in each case saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;C₃₋₈-cycloalkyl, in each case mono- or polysubstituted or unsubstituted;aryl or heteroaryl, in each case unsubstituted or mono- orpolysubstituted; aryl, heteroaryl or C₃₋₈-cycloalkyl bonded viaC₁₋₃-alkyl and in each case unsubstituted or mono- or polysubstituted;

X represents (C⁵R⁶)_(n); aryl or heteroaryl, in each case unsubstitutedor mono- or polysubstituted and in each case also bridged via aC₁₋₃-alkyl chain, which can be substituted; where n=0, 1, 2, 3 or 4;

A represents NH, ON, where in this case the bond between N and R⁴ is adouble bond, O or S,

l represents 1 or 2;

R⁴ represents C₁₋₅-alkyl, in each case saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;C₃₋₈-cycloalkyl, in each case mono- or polysubstituted or unsubstituted;aryl or heteroaryl, in each case mono- or polysubstituted orunsubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl bonded viaC₁₋₃-alkyl and in each case mono- or polysubstituted or unsubstituted;

R⁵ and R⁶ independently of one another represent H, C₁₋₅-alkyl, in eachcase saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; aryl, in each case mono- orpolysubstituted or unsubstituted,

with the proviso that X does not denote heteroaryl if l represents 1 andat the same time A represents O or S;

-   -   in the form of the racemate; the enantiomers, diastereomers,        mixtures of the enantiomers or diastereomers or an individual        enantiomer or diastereomer; the bases and/or salts of        physiologically acceptable acids or cations or in the form of        its solvates, in particular the hydrates thereof.

If a radical, for example X, can occur twice within one compound, it canalso assume different meanings.

The compounds according to the invention show good binding to the μreceptor and the ORL1 receptor, and also to other opioid receptors. Ithas been found, surprisingly, that the compounds are also goodinhibitors of the reuptake of noradrenaline and serotonin. They aretherefore also suitable for treatment of depressions and/or bulimiaand/or anorexia and/or catalepsy and/or for anxiolysis and/or forincreasing vigilance and/or libido.

The terms “C₁₋₅-alkyl” and “C₁₋₃-alkyl” in the context of this inventioninclude acyclic saturated or unsaturated hydrocarbon radicals, which canbe branched-chain or straight-chain and unsubstituted or mono- orpolysubstituted, having 1, 2, 3, 4 or 5 C atoms or, respectively, 1, 2or 3 C atoms, i.e. C₁₋₅-alkanyls, C₂₋₅-alkenyls and C₂₋₅-alkynyls or,respectively, C₁₋₃-alkanyls, C_(2,3)-alkenyls and C₂₋₃-alkynyls. In thiscontext, alkenyls have at least one C—C double bond and alkynyls have atleast one C—C triple bond. Alkyl is advantageously chosen from the groupwhich includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, ethylenyl(vinyl), ethynyl, propenyl (—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃),propynyl (—CH—CH≡CH, —C≡C—CH₃), 1,1-dimethylethyl, 1,1-dimethylpropyl,butenyl, butynyl, pentenyl and pentynyl.

The term “cycloalkyl” or “C₃₋₈-cycloalkyl” for the purpose of thisinvention denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbonatoms, it being possible for the hydrocarbons to be saturated orunsaturated (but not aromatic), unsubstituted or mono- orpolysubstituted. In respect of cycloalkyl, the expression also includessaturated or unsaturated (but not aromatic) cycloalkyls in which one ortwo carbon atoms are replaced by a heteroatom S, N or O. C₃₋₈-Cycloalkylis advantageously chosen from the group which contains cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and alsotetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl,piperazinyl, pyrazolinonyl and pyrrolidinyl.

The expression (CH₂)₃₋₆ is to be understood as meaning —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—.

The term “aryl” in the context of this invention denotes carbocyclicring systems having at least one aromatic ring but without heteroatomsin only one of the rings, inter alia phenyls, naphthyls andphenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.The aryl radicals can also be fused with further saturated, (partly)unsaturated or aromatic ring systems. Each aryl radical can beunsubstituted or mono- or polysubstituted, it being possible for thesubstituents on the aryl to be identical or different and in any desiredand possible position of the aryl. Phenyl or naphthyl radicals areparticularly advantageous.

The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromaticradical which contains at least 1, optionally also 2, 3, 4 or 5heteroatoms, the heteroatoms being identical or different and it beingpossible for the heterocyclic radical to be unsubstituted or mono- orpolysubstituted; in the case of substitution on the heterocyclicradical, the substituents can be identical or different and can be inany desired and possible position of the heteroaryl. The heterocyclicradical can also be part of a bi- or polycyclic system. Preferredheteroatoms are nitrogen, oxygen and sulfur. It is preferable for theheteroaryl radical to be chosen from the group which contains pyrrolyl,indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl),benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl,benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl,isoquinolinyl, isothiazolyl, triazolyl, triazinyl, quinazolinyl,carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, it being possiblefor the bond to the compounds of the general structure I to be via anydesired and possible ring member of the heteroaryl radical.

In connection with “alkyl”, the expression “substituted” in the contextof this invention is understood as meaning replacement of one or morehydrogen radicals by F, Cl, Br, I, —CN, ═O, ═S, NH₂, NH-alkyl, NH-aryl,NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl,NH-alkyl-OH, N(alkyl)₂, N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂,N(cycloalkyl)₂, N(alkyl-OH)₂, NH(C═O)alkyl, NH(C═O)aryl, NO₂, SH,S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl,S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl,O-alkyl-aryl, O-alkyl-heteroaryl, O-cycloalkyl, O-alkyl-OH, CHO,C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl, C(═O)aryl, C(═S)aryl,C(═O)C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl, C(═O)-heteroaryl,C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO₂H, CO₂-alkyl,CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NHaryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, SO-alkyl, SO₂-alkyl,SO₂NH₂, SO₃H, PO(O—C₁₋₆-alkyl)₂, cycloalkyl, aryl or heteroaryl,polysubstituted radicals being understood as meaning those radicalswhich are substituted several times, e.g. two or three times, either ondifferent or on the same atoms, for example three times on the same Catom, as in the case of CF₃ or —CH₂CF₃, or at different places, as inthe case of —CH(OH)—CH═CH—CHCl₂. Polysubstitution can be with the sameor with different substituents. A substituent can also optionally besubstituted in its turn; thus —Oalkyl, inter alia, also includes—O—CH₂—CH₂—O—CH₂—CH₂—OH.

In respect of “aryl”, “heteroaryl” and “cycloalkyl”, in the context ofthis invention “mono- or polysubstituted” is understood as meaningreplacement, once or several times, e.g. two, three, four or five times,of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN,NH₂, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl)₂,N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂, N(cycloalkyl)₂, N(alkyl-OH)₂, NO₂,SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl,S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl,O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl,O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl,C(═O)aryl, C(═S)aryl, C(═O)—C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl,C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl,CO₂H, CO₂-alkyl, CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NHaryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, S(O)-alkyl, S(O)-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, CF₃, ═O, ═S; —O—CH₂—CH₂—O—; alkyl,cycloalkyl, aryl and/or heteroaryl; on one or optionally different atoms(it being possible for a substituent optionally to be substituted in itsturn). Polysubstitution here is with the same or with differentsubstituents.

The expression salt is to be understood as meaning any form of theactive compound according to the invention in which this assumes anionic form or is charged and is coupled with a counter-ion (a cation oranion) or is in solution. This is also to be understood as meaningcomplexes of the active compound with other molecules and ions, inparticular complexes which are complexed via ionic interactions. Inparticular, by these there are understood (and this is also a preferredembodiment of this invention) physiologically acceptable salts, inparticular physiologically acceptable salts with cations or bases andphysiologically acceptable salts with anions or acids or also a saltformed with a physiologically acceptable acid or a physiologicallyacceptable cation.

In the context of this invention, the expression of physiologicallyacceptable salt with anions or acids is understood as meaning at leastone of the compounds according to the invention—usually protonated, forexample on the nitrogen—as the cation with at least one anion, which arephysiologically acceptable—especially when used in humans and/ormammals. In particular, in the context of this invention by this thereis understood the salt formed with a physiologically acceptable acid,namely salts of the particular active compound with inorganic or organicacids which are physiologically acceptable—especially when used inhumans and/or mammals. Examples of physiologically acceptable salts ofparticular acids are salts of: hydrochloric acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaricacid, lactic acid, citric acid, glutamic acid, saccharic acid,monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,α-liponic acid, acetylglycine, phosphoric acid, maleic acid, malonicacid, hippuric acid and/or aspartic acid. The hydrochloride salt, thecitrate and the hemicitrate are particularly preferred.

In the context of this invention, the expression of salt formed with aphysiologically acceptable acid is understood as meaning salts of theparticular active compound with inorganic or organic acids which arephysiologically acceptable—especially when used in humans and/ormammals. The hydrochloride and the citrate are particularly preferred.Examples of physiologically acceptable acids are: hydrochloric acid,hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid,fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid,monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,α-liponic acid, acetylglycine, hippuric acid and/or aspartic acid.

In the context of this invention, the expression of physiologicallyacceptable salt with cations or bases is understood as meaning salts ofat least one of the compounds according to the invention—usually of a(deprotonated) acid—as the anion with at least one preferably inorganiccation which are physiologically acceptable—especially when used inhumans and/or mammals. The salts of the alkali metals and alkaline earthmetals and also ammonium salts are particularly preferred, butespecially (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesiumor calcium salts.

In the context of this invention, the expression of salt formed with aphysiologically acceptable cation is understood as meaning salts of atleast one of the particular compounds as the anion with at least oneinorganic cation which is physiologically acceptable—especially whenused in humans and/or mammals. The salts of the alkali metals andalkaline earth metals and also ammonium salts are particularlypreferred, but especially (mono-) or (di-)sodium, (mono-) or(di-)potassium, magnesium or calcium salts.

For a preferred embodiment of the substituted cyclohexyl-1,4-diaminederivatives according to the invention,

-   -   R¹ and R² independently of one another represent H; C₁₋₅-alkyl,        saturated or unsaturated, branched or unbranched, mono- or        polysubstituted or unsubstituted;    -   or the radicals R¹ and R² together form a ring and denote        CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆,    -   wherein R¹⁰ denotes H; C₁₋₅-alkyl, saturated or unsaturated,        branched or unbranched, mono- or polysubstituted or        unsubstituted.

Particularly preferred substituted cyclohexyl-1,4-diamine derivativesare those wherein R¹ and R² independently of one another represent CH₃or H, where R¹ and R² do not simultaneously denote H, or R¹ and R²represent CH₂CH₂OCH₂CH₂, (CH₂)₄, (CH₂)₅ or (CH₂)₆.

Substituted cyclohexyl-1,4-diamine derivatives which are furthermorepreferred are those wherein

-   -   R³ represents cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl,        anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl,        benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl,        pyridyl, pyrimidyl or pyrazinyl, in each case unsubstituted or        mono- or polysubstituted; C₅₋₆-cycloalkyl, phenyl, naphthyl,        anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl,        benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl,        pyrrolyl, pyrimidyl or pyrazinyl bonded via a saturated,        unbranched C₁₋₂-alkyl group and in each case unsubstituted or        mono- or polysubstituted;    -   in particular    -   R³ denotes phenyl, furyl, thiophenyl, naphthyl, benzyl,        benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl,        pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl, in each case        unsubstituted or mono- or polysubstituted; phenyl, furyl or        thiophenyl bonded via a saturated, unbranched C₁₋₂-alkyl group        and in each case unsubstituted or mono- or polysubstituted.        Particularly preferred substituted cyclohexyl-1,4-diamine        derivatives are those wherein R³ represents phenyl, phenethyl,        thiophenyl, pyridyl or benzyl, in each case substituted or        unsubstituted, particularly preferably phenyl, thiophenyl,        4-chlorobenzyl, benzyl, 3-chlorobenzyl, 4-methylbenzyl,        2-chlorobenzyl, 4-fluorobenzyl, 3-methylbenzyl, 2-methylbenzyl,        3-fluorobenzyl, 2-fluorobenzyl or phenethyl.

Substituted cyclohexyl-1,4-diamine derivatives which are moreoverpreferred are those in which R⁴ represents C₁₋₅-alkyl, cyclohexyl,cyclopentyl, cyclobutyl, cycloheptyl, cyclooctyl, phenyl, benzyl,naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furanyl,isothiazolyl, imidazolyl, triazolyl, triazinyl, pyrazolyl, benzofuranyl,benzodioxolanyl, isoquinolinyl, phthalazinyl, benzo[1,2,5]thiadiazolyl,benzothiazolyl, benzotriazolyl, quinolinyl, carbazolyl, isoxazolyl,oxazolyl, indolyl, indanyl, benzodioxanyl, indazolyl, benzimidazolyl,pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in each case unsubstituted ormono- or polysubstituted; phenyl, naphthyl, anthracenyl, thiophenyl,benzothiophenyl. pyridyl, furyl, benzofuranyl, indolyl, indanyl,benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bonded via a saturated,unbranched substituted or unsubstituted C₁₋₂-alkyl group and in eachcase unsubstituted or mono- or polysubstituted,

in particular

R⁴ represents C₁₋₅-alkyl, branched or unbranched, saturated orunsaturated, cyclohexyl, cyclopentyl, phenyl, benzyl, naphthyl,thiophenyl, benzothiophenyl, furanyl, pyrazolyl, benzofuranyl,isoquinolinyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoxazolyl,oxazolyl, indolyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in eachcase unsubstituted or mono- or polysubstituted, C(O)phenyl, benzyl orphenethyl, in each case unsubstituted or mono- or polysubstituted.

Substituted cyclohexyl-1,4-diamine derivatives which are particularlypreferred are those in which R⁴ represents phenyl, C(O)phenyl,C₁₋₅-alkyl, branched or unbranched, saturated or unsaturated, benzyl,pyridyl, pyrimidinyl or indolyl, in each case unsubstituted or mono- orpolysubstituted.

Substituted cyclohexyl-1,4-diamine derivatives which are also preferredare those in which X represents (CR⁵R⁶)_(n), phenyl, pyridyl, naphthyl,thiophenyl, furyl, pyrimidinyl or indolyl, in each case unsubstituted ormono- or polysubstituted and in each case also bridged via a C₁₋₃-alkylchain, which can be substituted; where n=0, 1, 2, 3 or 4

and

R⁵, R⁶ independently of one another represent H, C₁₋₅-alkyl, in eachcase saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; phenyl, mono- or polysubstituted orunsubstituted.

Particularly preferred substituted cyclohexyl-1,4-diamine derivativesare those in which X represents vinylbenzyl, C₁₋₅-alkyl, branched orunbranched, saturated or unsaturated, phenethyl, phenyl, benzyl orpyridyl, in each case unsubstituted or mono- or polysubstituted.

Very particularly preferred substituted cyclohexyl-1,4-diaminederivatives are those from the group consisting of

-   benzoic acid    2-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-benzyl    ester-   4-chloro-N-(2-{4-[1-(4-dimethylamino-4-phenyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-benzamide-   N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide-   acetic acid    (4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-phenyl-methyl    ester-   benzoic acid    2-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl    ester-   acetic acid    [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-phenoxy-benzamide-   benzoic acid    2-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-benzyl    ester-   benzoic acid    2-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-benzyl    ester-   benzoic acid 2-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-benzyl    ester-   benzoic acid 2-(4-dimethylamino-4-phenyl-cyclohexylcarbamoyl)-benzyl    ester-   2-(3-chloro-phenoxy)-N-(4-dimethylamino-4-phenyl-cyclohexyl)-acetamide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide-   benzoic acid    2-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-benzyl    ester-   benzoic acid    2-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-benzyl ester-   benzoic acid    2-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-benzyl    ester-   2-benzylsulfanyl-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-acetamide-   benzoic acid    2-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-benzyl    ester-   N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-phenoxy-butyramide-   N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-phenoxy-acetamide-   benzoic acid    2-(4-benzyl-4-pyrrolidin-1-yl-cyclohexylcarbamoyl)-benzyl ester-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenoxy-acetamide-   4-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   benzoic acid    2-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl    ester-   N-(4-dimethylamino-4-phenyl-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide-   5-(2,5-dimethyl-phenoxy)-2,2-dimethyl-pimelic acid    [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-amide-   benzoic acid    2-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl    ester-   4-{1-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-chloro-phenoxy)-2-methyl-propionamide-   2-(2-chloro-phenoxy)-N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-methyl-propionamide-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-acetamide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-benzamide-   2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-acetamide-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide-   2-(3-chloro-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acetamide-   2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-benzamide-   2-(2-chloro-phenoxy)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-methyl-propionamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide-   2-benzyloxy-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide-   acetic acid    [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-methyl    ester-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide-   acetic acid    [4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methyl    ester-   2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide-   2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-benzamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide-   2-benzyloxy-N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(3-chloro-phenoxy)-acetamide-   acetic acid    (4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-methyl ester-   2-benzylsulfanyl-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide-   benzoic acid    2-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-benzyl ester-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-butyramide-   acetic acid    [4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide-   acetic acid    (4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-phenyl-methyl ester-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide-   2-benzylsulfanyl-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-methoxy-acetamide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenylamino-benzamide-   2-benzylsulfanyl-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide-   2-benzyloxy-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   2-benzyloxy-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-acetamide-   2-benzylsulfanyl-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   4-{1-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-butyramide-   2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide-   acetic acid (4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-methyl    ester-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-phenoxy-butyramide-   4-{1-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide-   benzoic acid    2-[2-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-ethyl]-phenyl    ester-   acetic acid    (4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-phenyl-methyl ester-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-phenoxy-butyramide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide-   2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenylamino-benzamide-   acetic acid    [4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   acetic acid    1-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl    ester-   N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide-   N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   acetic acid    [4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-phenoxy-propionamide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   4-(4-chloro-2-methyl-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-butyramide-   acetic acid    [4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   N-(4-dimethylamino-4-phenethyl-cyclohexyl)-4-phenoxy-butyramide-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide-   2-phenoxy-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide-   4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-butyramide-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide-   2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide-   acetic acid    [4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methyl    ester-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide-   acetic acid 1-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-ethyl    ester-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide-   4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-butyramide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   N-(4-dimethylamino-4-phenethyl-cyclohexyl)-2-phenoxy-propionamide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-ethoxy-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide-   2-benzyloxy-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   benzoic acid 2-(4-azepan-1-yl-4-benzyl-cyclohexylcarbamoyl)-benzyl    ester-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide-   4-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-butyric acid methyl    ester-   2-(4-chloro-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acetamide-   acetic acid    [4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   acetic acid    [4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl    ester-   4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-phenoxy-butyramide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide-   benzoic acid    2-{2-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl}-phenyl    ester-   benzoic acid    2-[2-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]-phenyl    ester-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenoxy-nicotinamide-   acetic acid    [4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methyl    ester-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide-   N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-2-phenoxy-propionamide-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-phenoxy-acetamide-   benzoic acid    2-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-benzyl ester-   4-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-butyric    acid methyl ester-   benzoic acid    2-[2-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]-phenyl    ester-   4-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   acetic acid    1-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-1-methyl-ethyl    ester-   acetic acid    [4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methyl    ester-   benzoic acid    2-{2-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}-phenyl    ester-   acetic acid    1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethyl    ester-   N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-phenoxy-acetamide-   4-chloro-N-(2-{4-[1-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-benzamide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-isopropylideneaminooxy-propionamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acid    ethyl ester-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-(pyrimidin-2-ylsulfanyl)-acetamide-   acetic acid    1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethyl    ester-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acid    ethyl ester-   4-phenoxy-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide-   acetic acid    1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethyl    ester-   5-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-pimelic    acid methyl ester-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-3-methoxy-propionamide-   acetic acid    1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethyl    ester-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide-   5-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-pimelic    acid methyl ester-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-methylsulfanyl-acetamide-   acetic acid    1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethyl    ester-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-methoxy-acetamide-   N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-succinic acid ethyl ester-   5-(2,5-dimethyl-phenoxy)-2,2-dimethyl-pimelic acid    (4-azepan-1-yl-4-benzyl-cyclohexyl)-amide-   N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-phenoxy-propionamide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-methoxy-acetamide-   4-(4-chloro-2-methyl-phenoxy)-N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-butyramide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-phenoxy-butyramide-   acetic    acid-1-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethyl    ester-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide-   N-(2-{4-[1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-4-chloro-benzamide-   acetic acid    1-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-ethyl ester-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinic acid    methyl ester-   3-(4-benzyloxy-3-methoxy-phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-acrylamide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide-   4-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-3-(4-benzyloxy-3-methoxy-phenyl)-acrylamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-methoxy-acetamide-   acetic acid (4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-methyl    ester-   4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-butyramide-   N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide-   2-phenylamino-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-benzamide-   N-(2-{4-[1-(4-benzyl-4-pyrrolidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-4-chloro-benzamide-   4-chloro-N-[2-(4-{1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   acetic acid    [4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-methyl    ester-   acetic acid    [4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-methyl    ester-   acetic acid    [4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl    ester-   acetic acid    [4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl    ester-   4-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-butyric    acid methyl ester-   acetic acid 1-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-ethyl    ester-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acrylamide-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acrylamide-   acetic acid    [4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-methyl    ester-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acrylamide-   N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-2-phenylamino-benzamide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-isopropylideneaminooxy-propionamide-   4-chloro-N-(2-{4-[1-methyl-1-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-ethyl)-benzamide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-isopropylideneaminooxy-propionamide-   N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide-   N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-succinic acid methyl ester-   benzoic acid    2-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-benzyl ester-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acid    methyl ester-   4-chloro-N-(2-{4-[1-methyl-1-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-ethyl)-benzamide-   5-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-pimelic    acid methyl ester-   4-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-butyric acid    methyl ester-   acetic acid    1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl    ester-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinic acid    methyl ester-   4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-succinic acid    methyl ester-   acetic acid    1-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl    ester-   acetic acid    1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl    ester-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-phenylamino-benzamide-   acetic acid 1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl    ester-   4-chloro-N-[2-(4-{1-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide-   acetic acid    1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl    ester-   4-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   4-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-succinic acid methyl ester-   acetic acid    1-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-ethyl    ester-   4-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric    acid methyl ester-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acrylamide-   benzoic acid    2-{2-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}-phenyl    ester-   4-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-butyric acid    methyl ester-   acetic acid    1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-ethyl    ester-   3-(4-benzyloxy-3-methoxy-phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acrylamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-ethoxy-acetamide-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acrylamide-   3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acrylamide-   2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide    hydrochloride, more polar diastereoisomer-   2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide    hydrochloride, less polar diastereoisomer-   N-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramide    hydrochloride, more polar diastereoisomer-   N-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramide    hydrochloride, less polar diastereoisomer    in the form of the racemate; the enantiomers, diastereomers,    mixtures of the enantiomers or diastereomers or an individual    enantiomer or diastereomer; the bases and/or salts of    physiologically acceptable acids or cations.

The substances according to the invention have an action, for example,on the μ-opioid receptor, which is relevant in connection with variousdiseases, so that they are suitable as a pharmaceutical active compoundin a medicament. The invention therefore also provides medicamentscomprising at least one substituted cyclohexyl-1,4-diamine derivativeaccording to the invention and optionally suitable additives and/orauxiliary substances and/or optionally further active compounds.

In addition to at least one substituted cyclohexyl-1,4-diaminederivative according to the invention, the medicaments according to theinvention optionally comprise suitable additives and/or auxiliarysubstances, thus also carrier materials, fillers, solvents, diluents,dyestuffs and/or binders, and can be administered as liquid medicamentforms in the form of injection solutions, drops or juices, as semi-solidmedicament forms in the form of granules, tablets, pellets, patches,capsules, plasters/spray plasters or aerosols. The choice of theauxiliary substances etc. and the amounts thereof to be employed dependon whether the medicament is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucous membranes or into the eyes. Formulationsin the form of tablets, coated tablets, capsules, granules, drops,juices and syrups are suitable for oral administration, and solutions,suspensions, easily reconstitutable dry formulations and sprays aresuitable for parenteral, topical and inhalatory administration.Substituted cyclohexyl-1,4-diamine derivatives according to theinvention in a depot, in dissolved form or in a plaster, optionally withthe addition of agents which promote penetration through the skin, aresuitable formulations for percutaneous administration. Formulation formswhich can be used orally or percutaneously can release the substitutedcyclohexyl-1,4-diamine derivatives according to the invention in adelayed manner. The substituted cyclohexyl-1,4-diamine derivativesaccording to the invention can also be used in parenteral long-termdepot forms, such as e.g. implants or implanted pumps. Other furtheractive compounds known to the expert can in principle be added to themedicaments according to the invention.

The amount of active compound to be administered to the patient variesaccording to the weight of the patient, the mode of administration, theindication and the severity of the disease. 0.00005 to 50 mg/kg,preferably 0.01 to 5 mg/kg of at least one substitutedcyclohexyl-1,4-diamine derivative according to the invention areconventionally administered.

For all the above forms of the medicaments according to the invention,it is particularly preferable if the medicament also comprises, inaddition to at least one substituted cyclohexyl-1,4-diamine derivative,a further active compound, in particular an opioid, preferably a potentopioid, in particular morphine, or an anaesthetic, preferablyhexobarbital or halothane.

In a preferred form of the medicament, a substitutedcyclohexyl-1,4-diamine derivative according to the invention containedtherein is in the form of a pure diastereomer and/or enantiomer, aracemate or a non-equimolar or equimolar mixture of the diastereomersand/or enantiomers.

The ORL1 receptor, and also the other opioid receptors, have beenidentified in particular in the pain event. Substitutedcyclohexyl-1,4-diamine derivatives according to the invention canaccordingly be used for the preparation of a medicament for treatment ofpain, in particular acute, neuropathic or chronic pain.

The invention therefore also provides the use of a substitutedcyclohexyl-1,4-diamine derivative according to the invention for thepreparation of a medicament for treatment of pain, in particular acute,visceral, neuropathic or chronic pain.

The invention also provides the use of a substitutedcyclohexyl-1,4-diamine derivative according to the invention for thepreparation of a medicament for treatment of anxiety states, of stressand stress-associated syndromes, depressions, epilepsy, Alzheimer'sdisease, senile dementia, catalepsy, general cognitive dysfunctions,learning and memory disorders (as a nootropic), withdrawal symptoms,alcohol and/or drug and/or medicament abuse and/or dependency, sexualdysfunctions, cardiovascular diseases, hypotension, hypertension,tinnitus, pruritus, migraine, impaired hearing, deficient intestinalmotility, impaired food intake, anorexia, obesity, locomotor disorders,diarrhea, cachexia, urinary incontinence and as a muscle relaxant,anticonvulsive or anaesthetic and for co-administration with treatmentwith an opioid analgesic or with an anaesthetic, for diuresis orantinatriuresis, anxiolysis, for modulation of movement activity, formodulation of neurotransmitter secretion and treatment ofneurodegenerative diseases associated therewith, for treatment ofwithdrawal symptoms and/or for reducing the addiction potential ofopioids.

In this context, in one of the above uses it may be preferable for asubstituted cyclohexyl-1,4-diamine derivative used to be in the form ofa pure diastereomer and/or enantiomer, a racemate or a non-equimolar orequimolar mixture of the diastereomers and/or enantiomers.

The invention also provides a method for treatment, in particular in oneof the abovementioned indications, of a non-human mammal or human whichor who requires treatment of pain, in particular chronic pain, byadministration of a therapeutically active dose of a substitutedcyclohexyl-1,4-diamine derivative according to the invention or of amedicament according to the invention.

The invention also provides a process for the preparation of thesubstituted cyclohexyl-1,4-diamine derivatives according to theinvention as described in the following description and examples.

The radicals R^(O1) and R⁰² have the meaning given for R¹ and R² forcompounds according to formula I according to the invention, and canadditionally independently of one another represent a protective group.The other radicals have the meaning given in formula I:

The diverse methods known to the expert for the preparation of amidesare in principle suitable for the preparation of the substancesaccording to the invention.

The process according to the invention is preferably based on linkingsubstituted cyclohexane-1,4-diamines (WO 02090317) with suitablecarboxylic acids and/or carboxylic acid derivatives, in particularcarboxylic acid chlorides or bromides, and converting them intocompounds according to the invention in this way.

Polar or nonpolar aprotic solvents to which an organic or inorganicauxiliary base, preferably tertiary amines, such as triethylamine,diusopropylethylamine or DMAP, has been added are employed in reactionswith acid chlorides and bromides. In addition to such amines, pyridine,for example, is also suitable as a base and as a solvent. Preferably,acid chlorides are reacted with amines at −30 to +40° C. in methylenechloride or chloroform in the presence of triethylamine or pyridine andoptionally catalytic amounts of DMAP. The entire range of methods knownto the expert for the preparation of amides is also available for thereaction of carboxylic acids with a substituted cyclohexane-1,4-diamine(WO 02090317). The use of organic or inorganic dehydrating agents, suchas e.g. a molecular sieve, magnesium sulfate, sulfuric acid orcarboduimides, such as DCC or DIC, the latter optionally in the presenceof HOBt, is advantageous in this context. These reactions are alsopreferably carried out in polar or nonpolar aprotic solvents attemperatures of between −30 and +110° C., preferably −10 and +40° C. Ifappropriate, the protective groups are then split off.

EXAMPLES

The following examples serve to explain the invention in more detail,but do not limit the general inventive idea.

The yields of the compounds prepared are not optimized.

All the temperatures are uncorrected.

The term “ether” denotes diethyl ether, “EA” denotes ethyl acetate and“MC” denotes methylene chloride. The term “equivalent” means equivalentsubstance amount, “m.p.” denotes melting point or melting range,“decomp.” denotes decomposition, “RT” denotes room temperature, “abs.”denotes absolute (anhydrous), “rac.” denotes racemic, “conc.” denotesconcentrated, “min” denotes minutes, “h” denotes hours, “d” denotesdays, “vol. %” denotes per cent by volume, “wt. %” denotes per cent byweight and “M” is the concentration stated in mol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was employed asthe stationary phase for the column chromatography.

The thin layer chromatography analyses were carried out with HPTLCprecoated plates, silica gel 60 F 254 from E. Merck, Darmstadt.

The mixture ratios of mobile phases for chromatographic analyses arealways stated in volume/volume.

The compounds employed in the following either were commerciallyobtainable or their preparation is known from the prior art or has beendeduced from the prior art in a manner obvious to the expert.

General Instructions:

0.1 mmol of an acid chloride which has been prepared from thecorresponding carboxylic acids by methods known to the expert (seeTable 1) was added to 0.1 mmol of the cyclohexane-1,4-diamine in thepresence of 1.05 equivalents of triethylamine. The mixture was stirredfor 12 h and a 1 M sodium carbonate solution was then added. The productwas obtained by extraction with in each case 3×2 ml methylene chlorideand removal of the solvent.

The carboxylic acids employed for the last step for the examples arenamed in Table 1. TABLE 1 Names of the example compounds and structuresof the carboxylic acids employed in the last step Compound Acid employedName Example 1

benzoic acid 2-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]- benzyl ester Example 2

4-chloro-N-(2-{4-[1-(4- dimethylamino-4-phenyl- cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)- benzamide Example 3

N-(4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide Example 4

acetic acid (4-dimethylamino- 4-thiophen-2-yl-cyclohexylcarbamoyl)-phenyl- methyl ester Example 5

benzoic acid 2-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl ester Example 6

acetic acid [4-dimethylamino- 4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 7

N-[4-dimethylamino-4-(3- fluoro-phenyl)-cyclohexyl]-2- phenoxy-benzamideExample 8

benzoic acid 2-[4- dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]- benzyl ester Example 9

benzoic acid 2-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]- benzyl ester Example 10

benzoic acid 2-(4-benzyl-4- dimethylamino- cyclohexylcarbamoyl)-benzylester Example 11

benzoic acid 2-(4- dimethylamino-4-phenyl- cyclohexylcarbamoyl)-benzylester Example 12

2-(3-chloro-phenoxy)-N-(4- dimethylamino-4-phenyl- cyclohexyl)-acetamideExample 13

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro- benzamide Example 14

benzoic acid 2-[4- dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]- benzyl ester Example 15

benzoic acid 2-(4- dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-benzyl ester Example 16

benzoic acid 2-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]- benzyl ester Example 17

2-benzylsulfanyl-N-(4- dimethylamino-4-thiophen-2-yl-cyclohexyl)-acetamide Example 18

benzoic acid 2-[4- dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]- benzyl ester Example 19

N-(4-dimethylamino-4-phenyl- cyclohexyl)-4-phenoxy- butyramide Example20

N-(4-dimethylamino-4- thiophen-2-yl-cyclohexyl)-2- phenoxy-acetamideExample 21

benzoic acid 2-(4-benzyl-4- pyrrolidin-1-yl- cyclohexylcarbamoyl)-benzylester Example 22

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2- phenoxy-acetamideExample 23

4-[4-dimethylamino-4-(3- fluoro-phenyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 24

benzoic acid 2-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl ester Example 25

N-(4-dimethylamino-4-phenyl- cyclohexyl)-2-(2-methoxy- ethoxy)-acetamideExample 26

5-(2,5-dimethyl-phenoxy)-2,2- dimethyl-pimelic acid [4-dimethylamino-4-(3-fluoro- phenyl)-cyclohexyl]-amide Example 27

benzoic acid 2-[4-(2-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzyl ester Example 28

4-{1-[4-(2-chloro-benzyl)-4- dimethylamino- cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide Example 29

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(2-chloro-phenoxy)-2-methyl- propionamide Example 30

2-(2-chloro-phenoxy)-N-[4- dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-methyl- propionamide Example 31

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro- benzamide Example 32

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2- phenoxy-acetamideExample 33

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro- benzamide Example 34

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-2- phenoxy-benzamideExample 35

2-(4-chloro-phenoxy)-N-[4- dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide Example 36

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-2- phenoxy-acetamideExample 37

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2- phenoxy-acetamideExample 38

2-(3-chloro-phenoxy)-N-(4- dimethylamino-4-phenethyl-cyclohexyl)-acetamide Example 39

2-(3-chloro-phenoxy)-N-[4- dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide Example 40

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2- phenoxy-benzamideExample 41

2-(2-chloro-phenoxy)-N-[4- dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-methyl- propionamide Example 42

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-phenoxy-propionamide Example 43

2-benzyloxy-N-[4- dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide Example 44

acetic acid [4-dimethylamino- 4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-methyl ester Example 45

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide Example 46

acetic acid [4-(2-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl- methyl ester Example 47

2-(4-chloro-phenoxy)-N-[4- dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide Example 48

2-(3-chloro-phenoxy)-N-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide Example 49

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-2- phenoxy-benzamideExample 50

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide Example 51

2-benzyloxy-N-[4-(2-chloro- benzyl)-4-dimethylamino-cyclohexyl]-acetamide Example 52

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(3-chloro-phenoxy)-acetamide Example 53

acetic acid (4-dimethylamino- 4-thiophen-2-yl-cyclohexylcarbamoyl)-methyl ester Example 54

2-benzylsulfanyl-N-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide Example 55

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide Example 56

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide Example 57

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro- benzamide Example 58

benzoic acid 2-(4-benzyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-benzylester Example 59

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-phenoxy-butyramide Example 60

acetic acid [4-dimethylamino- 4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 61

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2- phenoxy-acetamideExample 62

acetic acid (4-benzyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-phenyl-methyl ester Example 63

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide Example 64

2-benzylsulfanyl-N-[4-(3- chloro-benzyl)-4- dimethylamino-cyclohexyl]-acetamide Example 65

N-[4-dimethylamino-4-(3- fluoro-phenyl)-cyclohexyl]-2- methoxy-acetamideExample 66

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2-phenylamino-benzamide Example 67

2-benzylsulfanyl-N-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide Example 68

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-(4-chloro- phenoxy)-acetamideExample 69

2-benzyloxy-N-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexyl]-acetamide Example 70

2-benzyloxy-N-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide Example 71

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-phenoxy-propionamide Example 72

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2- phenoxy-acetamideExample 73

2-benzylsulfanyl-N-[4-(4- chloro-benzyl)-4- dimethylamino-cyclohexyl]-acetamide Example 74

4-{1-[4-dimethylamino-4-(4- fluoro-benzyl)- cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide Example 75

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-2-phenoxy-butyramide Example 76

2-(4-chloro-phenoxy)-N-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide Example 77

acetic acid (4-dimethylamino- 4-phenethyl- cyclohexylcarbamoyl)-methylester Example 78

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-4-phenoxy-butyramide Example 79

4-{1-[4-dimethylamino-4-(2- methyl-benzyl)- cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide Example 80

benzoic acid 2-[2-(4- dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-ethyl]- phenyl ester Example 81

acetic acid (4-benzyl-4- dimethylamino- cyclohexylcarbamoyl)-phenyl-methyl ester Example 82

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide Example 83

N-(4-benzyl-4-dimethylamino- cyclohexyl)-4-phenoxy- butyramide Example84

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro- benzamide Example 85

2-(4-chloro-phenoxy)-N-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide Example 86

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-phenylamino-benzamide Example 87

acetic acid [4-dimethylamino- 4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 88

acetic acid 1-[4- dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]- ethyl ester Example 89

N-(4-benzyl-4-pyrrolidin-1-yl- cyclohexyl)-2-(4-chloro-phenoxy)-acetamide Example 90

N-(4-phenyl-4-piperidin-1-yl- cyclohexyl)-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 91

acetic acid [4-dimethylamino- 4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 92

2-(3-chloro-phenoxy)-N-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide Example 93

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-phenoxy- propionamide Example94

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 95

4-(4-chloro-2-methyl-phenoxy)- N-(4-dimethylamino-4-phenethyl-cyclohexyl)- butyramide Example 96

acetic acid [4-dimethylamino- 4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 97

N-(4-dimethylamino-4- phenethyl-cyclohexyl)-4- phenoxy-butyramideExample 98

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide Example 99

2-phenoxy-N-(4-phenyl-4- piperidin-1-yl-cyclohexyl)- butyramide Example100

4-(4-chloro-2-methyl-phenoxy)- N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]- butyramide Example 101

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide Example 102

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide Example 103

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-phenoxy-propionamide Example 104

2-(4-chloro-phenoxy)-N-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide Example 105

acetic acid [4-(3-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl- methyl ester Example 106

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide Example 107

acetic acid 1-(4-benzyl-4- dimethylamino- cyclohexylcarbamoyl)-ethylester Example 108

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide Example 109

4-(4-chloro-2-methyl-phenoxy)- N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]- butyramide Example 110

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 111

N-(4-dimethylamino-4- phenethyl-cyclohexyl)-2- phenoxy-propionamideExample 112

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2- ethoxy-acetamideExample 113

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 114

N-(4-benzyl-4-dimethylamino- cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide Example 115

2-benzyloxy-N-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexyl]-acetamide Example 116

benzoic acid 2-(4-azepan-1-yl- 4-benzyl- cyclohexylcarbamoyl)-benzylester Example 117

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide Example 118

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-2- phenoxy-acetamideExample 119

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-2-(4-chloro-phenoxy)-acetamide Example 120

N-[4-dimethylamino-4-(4- methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide Example 121

4-(4-benzyl-4-dimethylamino- cyclohexylcarbamoyl)-butyric acid methylester Example 122

2-(4-chloro-phenoxy)-N-(4- dimethylamino-4-phenethyl-cyclohexyl)-acetamide Example 123

acetic acid [4-dimethylamino- 4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 124

acetic acid [4-(2-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester Example 125

4-chloro-N-[2-(4-{1-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethoxy}-phenyl)- ethyl]-benzamideExample 126

4-chloro-N-[2-(4-{1-[4- dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethoxy}-phenyl)- ethyl]-benzamideExample 127

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-4-phenoxy-butyramide Example 128

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-(2-methoxy- ethoxy)-acetamideExample 129

benzoic acid 2-{2-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]- ethyl}-phenyl ester Example 130

benzoic acid 2-[2-(4-benzyl-4- piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]- phenyl ester Example 131

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2-phenoxy-nicotinamide Example 132

acetic acid [4-dimethylamino- 4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl- methyl ester Example 133

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide Example 134

N-(4-benzyl-4-pyrrolidin-1-yl- cyclohexyl)-2-phenoxy- propionamideExample 135

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-2-phenoxy- acetamide Example136

benzoic acid 2-(4-phenyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-benzylester Example 137

4-[4-(3-chloro-benzyl)-4- dimethylamino- cyclohexylcarbamoyl]-butyricacid methyl ester Example 138

benzoic acid 2-[2-(4-phenyl-4- piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]- phenyl ester Example 139

4-[4-dimethylamino-4-(4- fluoro-benzyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 140

acetic acid 1-(4-benzyl-4- dimethylamino- cyclohexylcarbamoyl)-1-methyl-ethyl ester Example 141

acetic acid [4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl- methyl ester Example 142

benzoic acid 2-{2-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}- phenyl ester Example 143

acetic acid 1-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethyl ester Example 144

N-(4-azepan-1-yl-4-benzyl- cyclohexyl)-2-phenoxy- acetamide Example 145

4-chloro-N-(2-{4-[1-(4- dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-1- methyl-ethoxy]-phenyl}-ethyl)- benzamide Example146

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]-2-isopropylideneaminooxy- propionamide Example 147

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]- succinic acid ethylester Example 148

N-[4-dimethylamino-4-(4- fluoro-benzyl)-cyclohexyl]-2-(pyrimidin-2-ylsulfanyl)- acetamide Example 149

acetic acid 1-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1- methyl-ethyl ester Example 150

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]- succinic acid ethylester Example 151

4-phenoxy-N-(4-phenyl-4- piperidin-1-yl-cyclohexyl)- butyramide Example152

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide Example 153

acetic acid 1-(4-benzyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-1-methyl-ethyl ester Example 154

5-[4-dimethylamino-4-(4- methyl-benzyl)- cyclohexylcarbamoyl]-pimelicacid methyl ester Example 155

N-[4-dimethylamino-4-(4- methyl-benzyl)-cyclohexyl]-3-methoxy-propionamide Example 156

acetic acid 1-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethyl ester Example 157

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide Example 158

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide Example 159

5-[4-dimethylamino-4-(2- fluoro-benzyl)- cyclohexylcarbamoyl]-pimelicacid methyl ester Example 160

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-methylsulfanyl- acetamideExample 161

acetic acid 1-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethyl ester Example 162

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-2-methoxy- acetamide Example163

N-(4-morpholin-4-yl-4-phenyl- cyclohexyl)-succinic acid ethyl esterExample 164

5-(2,5-dimethyl-phenoxy)-2,2- dimethyl-pimelic acid (4-azepan-1-yl-4-benzyl- cyclohexyl)-amide Example 165

N-(4-azepan-1-yl-4-benzyl- cyclohexyl)-2-phenoxy- propionamide Example166

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide Example 167

N-[4-dimethylamino-4-(2- methyl-benzyl)-cyclohexyl]-2- methoxy-acetamideExample 168

4-(4-chloro-2-methyl-phenoxy)- N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-butyramide Example 169

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide Example 170

N-[4-dimethylamino-4-(4- methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide Example 171

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-4-phenoxy- butyramide Example172

acetic acid-1-[4-(2-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1- methyl-ethyl ester Example 173

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide Example 174

N-(2-{4-[1-(4-benzyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-1-methyl-ethoxyl-phenyl}-ethyl)- 4-chloro-benzamide Example 175

acetic acid 1-(4- dimethylamino-4-phenethyl- cyclohexylcarbamoyl)-ethylester Example 176

N-[4-dimethylamino-4-(3- fluoro-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide Example 177

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 178

N-[4-dimethylamino-4-(4- methyl-benzyl)-cyclohexyl]- succinic acidmethyl ester Example 179

3-(4-benzyloxy-3-methoxy- phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)- acrylamide Example 180

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide Example 181

4-[4-dimethylamino-4-(4- methyl-benzyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 182

N-(4-benzyl-4-dimethylamino- cyclohexyl)-3-(4-benzyloxy-3-methoxy-phenyl)-acrylamide Example 183

N-(4-benzyl-4-dimethylamino- cyclohexyl)-2-methoxy- acetamide Example184

acetic acid (4-morpholin-4-yl- 4-phenyl- cyclohexylcarbamoyl)-methylester Example 185

4-(4-chloro-2-methyl-phenoxy)- N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]- butyramide Example 186

N-(4-azepan-1-yl-4-benzyl- cyclohexyl)-2-(4-chloro- phenoxy)-acetamideExample 187

2-phenylamino-N-(4-phenyl-4- piperidin-1-yl-cyclohexyl)- benzamideExample 188

N-(2-{4-[1-(4-benzyl-4- pyrrolidin-1-yl- cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)- 4-chloro-benzamide Example 189

4-chloro-N-[2-(4-{1-[4-(4- chloro-benzyl)-4- dimethylamino-cyclohexylcarbamoyl]-1- methyl-ethoxy}-phenyl)-ethyl]- benzamide Example190

acetic acid [4-dimethylamino- 4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-methyl ester Example 191

acetic acid [4-dimethylamino- 4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-methyl ester Example 192

acetic acid [4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester Example 193

acetic acid [4-(3-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester Example 194

4-[4-(4-chloro-benzyl)-4- dimethylammo- cyclohexylcarbamoyl]-butyricacid methyl ester Example 195

acetic acid 1-(4-morpholin-4- yl-4-phenyl- cyclohexylcarbamoyl)-ethylester Example 196

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)- cyclohexyl]-acrylamide Example 197

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)- cyclohexyl]-acrylamide Example 198

acetic acid [4-dimethylamino- 4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-methyl ester Example 199

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]- acrylamide Example 200

N-(4-morpholin-4-yl-4-phenyl- cyclohexyl)-2-phenylamino- benzamideExample 201

N-[4-(4-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-isopropylideneaminooxy- propionamide Example 202

4-chloro-N-(2-{4-[1-methyl-1- (4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethoxy]- phenyl}-ethyl)-benzamide Example 203

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2-isopropylideneaminooxy- propionamide Example 204

N-(4-morpholin-4-yl-4-phenyl- cyclohexyl)-2-(5-trifluoromethyl-pyridin-2- ylsulfanyl)-acetamide Example 205

N-(4-phenyl-4-piperidin-1-yl- cyclohexyl)-succinic acid methyl esterExample 206

benzoic acid 2-(4-morpholin-4- yl-4-phenyl- cyclohexylcarbamoyl)-benzylester Example 207

N-[4-(3-chloro-benzyl)-4- dimethylamino-cyclohexyl]- succinic acidmethyl ester Example 208

4-chloro-N-(2-{4-[1-methyl-1- (4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-ethoxy]- phenyl}-ethyl)-benzamide Example 209

5-[4-(2-chloro-benzyl)-4- dimethylamino- cyclohexylcarbamoyl]-pimelicacid methyl ester Example 210

4-(4-phenyl-4-piperidin-1-yl- cyclohexylcarbamoyl)-butyric acid methylester Example 211

acetic acid 1-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]- ethyl ester Example 212

N-[4-dimethylamino-4-(3- methyl-benzyl)-cyclohexyl]- succinic acidmethyl ester Example 213

4-chloro-N-[2-(4-{1-[4- dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethoxy}-phenyl)- ethyl]-benzamideExample 214

N-[4-dimethylamino-4-(2- fluoro-benzyl)-cyclohexyl]- succinic acidmethyl ester Example 215

acetic acid 1-[4-(3-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl ester Example 216

acetic acid 1-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl ester Example 217

N-(4-benzyl-4-piperidin-1-yl- cyclohexyl)-2-phenylamino- benzamideExample 218

acetic acid 1-(4-benzyl-4- piperidin-1-yl- cyclohexylcarbamoyl)-ethylester Example 219

4-chloro-N-[2-(4-{1-[4-(3- chloro-benzyl)-4- dimethylamino-cyclohexylcarbamoyl]-1- methyl-ethoxy}-phenyl)-ethyl]- benzamide Example220

4-chloro-N-[2-(4-{1-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]- 1-methyl-ethoxy}-phenyl)- ethyl]-benzamideExample 221

acetic acid 1-[4- dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]- ethyl ester Example 222

4-[4-dimethylamino-4-(3- fluoro-benzyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 223

4-[4-dimethylamino-4-(3- methyl-benzyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 224

N-(4-morpholin-4-yl-4-phenyl- cyclohexyl)-succinic acid methyl esterExample 225

acetic acid 1-[4- dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]- ethyl ester Example 226

4-[4-dimethylamino-4-(2- fluoro-benzyl)- cyclohexylcarbamoyl]-butyricacid methyl ester Example 227

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]- acrylamide Example 228

benzoic acid 2-{2-[4-(4-chloro- benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}- phenyl ester Example 229

4-(4-morpholin-4-yl-4-phenyl- cyclohexylcarbamoyl)-butyric acid methylester Example 230

acetic acid 1-[4- dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]- ethyl ester Example 231

3-(4-benzyloxy-3-methoxy- phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)- acrylamide Example 232

N-[4-(2-chloro-benzyl)-4- dimethylamino-cyclohexyl]-2- ethoxy-acetamideExample 233

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]- acrylamide Example 234

3-(4-benzyloxy-3-methoxy- phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]- acrylamide

Some example compounds were synthesized on a larger scale.

Example 2352-(3-Chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamidehydrochloride, More Polar Diastereoisomer

A cis/trans mixture of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (800mg) was initially introduced into the reaction vessel with 540 μltriethylamine (1.05 molar equivalents) and catalytic amounts of DMAP(approx. 15 mg) in 20 ml methylene chloride, 790 mg(3-chlorophenoxy)acetyl chloride (1.05 molar equivalents) were addeddropwise at −20° C. and the mixture was stirred overnight, while warmingto room temperature. For working up, the mixture was rendered alkaline(pH>10) with one molar sodium hydroxide solution and extracted withdiethyl ether (3×20 ml), the combined extracts were dried over sodiumsulfate and filtered and the filtrate was concentrated to dryness. Thecrude product obtained (1.53 g) was chromatographed on silica gel(3.0×17 cm) with 100 ml diethyl ether followed by 500 ml diethylether/methanol (v:v=2:1). 346 mg of the more polar diastereoisomer of2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide wereobtained and, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate,were converted into the corresponding hydrochloride by addition of 16 μlwater and 110 μl chlorotrimethylsilane (322 mg of a white solid, m.p.220° C.).

Example 2362-(3-Chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamidehydrochloride, Less Polar Diastereoisomer

As described for Example 235, 356 mg of the less polar diastereoisomerof 2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamidewere also obtained and, as a solution in 5 ml 2-butanone and 10 ml ethylacetate, were converted into the corresponding hydrochloride by additionof 17 μl water and 117 μl chlorotrimethylsilane (338 mg of a whitesolid, m.p. 223-224.5° C.).

Example 237 N-(4-Dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramidehydrochloride, More Polar Diastereoisomer

As described for Example 235, a cis/trans mixture ofN,N-dimethyl-1-phenylcyclohexane-1,4-diamine (800 mg) was reacted with0.95 mg 4-phenoxybutyryl chloride and the crude product (1.48 g) wasisolated analogously. By chromatography on silica gel (3.0×19 cm) with100 ml diethyl ether followed by 400 ml diethyl ether/methanol(v:v=2:1), 450 mg of the more polar diastereoisomer ofN-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramide were obtainedand, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate, wereconverted into the corresponding hydrochloride by addition of 21.3 μlwater and 150 μl chlorotrimethylsilane (420 mg of a white solid, m.p.191-192° C.).

Example 238 N-(4-Dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramidehydrochloride, Less Polar Diastereoisomer

As described for Example 237, 575 mg of the less polar diastereoisomerof N-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramide were alsoobtained and, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate,were converted into the corresponding hydrochloride by addition of 27.2μl water and 190 μl chlorotrimethylsilane (530 mg of a white solid, m.p.194-197° C.).

Investigations of the activity of the compounds according to theinvention:

Measurement of the ORL1 Binding

The cyclohexane derivatives of the general formula I were investigatedin a receptor binding assay with ³H-nociceptin/orphanin FQ withmembranes from recombinant CHO-ORL1 cells. This test system wasconducted in accordance with the method described by Ardati et al. (Mol.Pharmacol., 51, 1997, p. 816-824). The concentration of³H-nociceptin/orphanin FQ in these experiments was 0.5 nM. The bindingassays were carried out with in each case 20 μg of membrane protein per200 μl batch in 50 mM hepes, pH 7.4, 10 mM MgCl₂ and 1 mM EDTA. Thebinding to the ORL1 receptor was determined using in each case 1 mgWGA-SPA beads (Amersham-Pharmacia, Freiburg) by incubation of the batchfor one hour at RT and subsequent measurement in a Trilux scintillationcounter (Wallac, Finland). The affinity is stated in Table 1 as thenanomolar K_(i) value in or % inhibition at c=1 μM.

Measurement of the μ Binding

The receptor affinity for the human μ-opiate receptor was determined ina homogeneous batch in microtitre plates. For this, dilution series ofthe particular substituted cyclohexyl-1,4-diamine derivative to betested were incubated in a total volume of 250 μl for 90 minutes at roomtemperature with a receptor membrane preparation (15-40 μg protein per250 μl incubation batch) of CHO-K1 cells, which express the humanμ-opiate receptor (RB-HOM receptor membrane preparation of NEN,Zaventem, Belgium), in the presence of 1 nmol/l of the radioactiveligand [³H]-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mgWGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia,Freiburg, Germany). 50 mmol/l Tris-HCl supplemented with 0.05 wt. %sodium azide and with 0.06 wt. % bovine serum albumin was used as theincubation buffer. 25 μmol/l naloxone was additionally added fordetermination of the non-specific binding. When the ninety minutes ofincubation time had ended, the microtitre plates were centrifuged off at1,000 g for 20 minutes and the radioactivity was measured in a β-counter(Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). Thepercentage displacement of the radioactive ligand from its binding tothe human vu-opiate receptor at a concentration of the test substancesof 1 μmol/l was determined and was stated as the percentage inhibition(% inhibition) of the specific binding. In some cases, on the basis ofthe percentage displacement by different concentrations of the compoundsof the general formula I to be tested, IC₅₀ inhibitory concentrationswhich cause 50 per cent displacement of the radioactive ligand werecalculated. By conversion by means of the Cheng-Prusoff relationship, Kivalues were obtained for the test substances.

Measurement of the Serotonin Reuptake

In order to be able to carry out these in vitro studies, synaptosomesare freshly isolated from rat brain areas. In each case a so-called “P₂”fraction, which is prepared in accordance with the instructions of Grayand Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76,79-88), is used. For the 5HT uptake, these vesicular particles areisolated from the medulla+pons region of male rat brains.

A detailed description of the method can be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert(1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

Measurement of the Noradrenaline Reuptake

In order to be able to carry out these in vitro studies, synaptosomesare freshly isolated from rat brain areas. In each case a so-called “P₂”fraction, which is prepared in accordance with the instructions of Grayand Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76,79-88), is used. For the NA uptake, these vesicular particles areisolated from the hypothalamus of male rat brains.

A detailed description of the method can be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert(1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

The following binding data were determined by way of example: μ-Opiatereceptor Compound [1 μM], % inhibition Example 1 106 Example 2 104Example 3 101 Example 4 100 Example 5 100 Example 6 99 Example 7 98Example 8 98 Example 9 98 Example 10 97 Example 11 97 Example 12 97Example 13 96 Example 14 96 Example 15 96 Example 16 96 Example 17 95Example 18 95 Example 19 95 Example 20 94 Example 21 94 Example 22 93Example 23 93 Example 24 92 Example 25 91 Example 26 91 Example 27 90Example 28 89 Example 29 89 Example 30 89 Example 31 89 Example 32 86Example 33 86 Example 34 85 Example 35 85 Example 36 85 Example 37 84Example 38 84 Example 39 84 Example 40 82 Example 41 82 Example 42 82Example 43 82 Example 44 81 Example 45 81 Example 46 80 Example 47 80Example 48 80 Example 49 79 Example 50 79 Example 51 79 Example 52 79Example 53 77 Example 54 77 Example 55 77 Example 56 77 Example 57 77Example 58 76 Example 59 76 Example 60 76 Example 61 75 Example 62 74Example 63 73 Example 64 73 Example 65 73 Example 66 73 Example 67 71Example 68 71 Example 69 71 Example 70 71 Example 71 70 Example 72 69Example 73 69 Example 74 69 Example 75 69 Example 76 69 Example 77 68Example 78 68 Example 79 67 Example 80 67 Example 81 66 Example 82 66Example 83 65 Example 84 65 Example 85 64 Example 86 64 Example 87 64Example 88 63 Example 89 63 Example 90 63 Example 91 63 Example 92 63Example 93 61 Example 94 61 Example 95 61 Example 96 61 Example 97 58Example 98 57 Example 99 57 Example 100 57 Example 101 57 Example 102 56Example 103 56 Example 104 56 Example 105 56 Example 106 55 Example 10755 Example 108 55 Example 109 55 Example 110 55 Example 111 54 Example112 54 Example 113 52 Example 114 52 Example 115 52 Example 116 51Example 117 51 Example 118 51 Example 119 50 Example 120 49 Example 12149 Example 122 49 Example 123 49 Example 124 48 Example 125 48 Example126 48 Example 127 47 Example 128 47 Example 129 47 Example 130 46Example 131 45 Example 132 45 Example 133 45 Example 134 44 Example 13544 Example 136 44 Example 137 44 Example 138 44 Example 139 43 Example140 43 Example 141 43 Example 142 42 Example 143 41 Example 144 41Example 145 41 Example 146 41 Example 235 68 Example 236 100 Example 23771 Example 238 100

ORL1 [1 μM], Compound % inhibition Example 1 44 Example 3 64 Example 478 Example 6 93 Example 7 84 Example 8 88 Example 9 60 Example 10 62Example 11 82 Example 12 97 Example 17 96 Example 19 99 Example 20 93Example 23 91 Example 25 70 Example 26 63 Example 44 56 Example 53 50Example 65 43 Example 78 52 Example 235 46 Example 236 99 Example 237 39Example 238 99

5HT uptake [10 μM], Example % inhibition 236 97 237 78 238 98

NA uptake [10 μM], Example % inhibition 235 40 236 87 237 56 238 77

Parenteral Solution of a Substituted cyclohexyl-1,4-diamine DerivativeAccording to the Invention

38 g of one of the substituted cyclohexyl-1,4-diamine derivativesaccording to the invention, here Example 1, are dissolved in 1 l ofwater for injection purposes at room temperature and the solution isthen adjusted to isotonic conditions by addition of anhydrous glucosefor injection purposes.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A cyclohexyl-1,4-diamine compound corresponding to formula I

wherein R¹ and R², independently of one another, represent H;C₁₋₅-alkyl, in each case saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted; C₃₋₈-cycloalkyl,in each case mono- or polysubstituted or unsubstituted; or aryl,C₃₋₈-cycloalkyl or heteroaryl bonded via C₁₋₃-alkyl and in each casemono- or polysubstituted or unsubstituted; or R¹ and R² together form aring and represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆, whereinR¹⁰ denotes H; C₁₋₅-alkyl, in each case saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;C₃₋₈-cycloalkyl, in each case mono- or polysubstituted or unsubstituted;aryl or heteroaryl, in each case mono- or polysubstituted orunsubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl bonded viaC₁₋₃-alkyl and in each case mono- or polysubstituted or unsubstituted;C(O)phenyl, C(O)heteroaryl, C(O)C₁₋₅-alkyl, in each case substituted orunsubstituted; R³ represents C₁₋₅-alkyl, in each case saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; C₃₋₈-cycloalkyl, in each case mono- or polysubstituted orunsubstituted; aryl or heteroaryl, in each case unsubstituted or mono-or polysubstituted; aryl, heteroaryl or C₃₋₈-cycloalkyl bonded viaC₁₋₃-alkyl and in each case unsubstituted or mono- or polysubstituted; Xrepresents (CR⁵R⁶)_(n); aryl or heteroaryl, in each case unsubstitutedor mono- or polysubstituted and in each case also bridged via aC₁₋₃-alkyl chain, which may be substituted; where n=0, 1, 2, 3, or 4; Arepresents NH, ON, wherein the bond between N and R⁴ is a double bond, Oor S, l represents 1 or 2; R⁴ represents C₁₋₅-alkyl, in each casesaturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; C₃₋₈-cycloalkyl, in each case mono- orpolysubstituted or unsubstituted; aryl or heteroaryl, in each case mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈-cycloalkyl orheteroaryl bonded via C₁₋₃-alkyl and in each case mono- orpolysubstituted or unsubstituted; R⁵ and R⁶ independently of one anotherrepresent H, C₁₋₅-alkyl, in each case saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; aryl, in eachcase mono- or polysubstituted or unsubstituted, provided if l represents1 and A represents O or S, then X is not heteroaryl; or an acid, base orphysiologically acceptable salt thereof.
 2. The cyclohexyl-1,4-diaminecompound of claim 1, wherein said compound is present in the form of apure enantiomer or pure diastereoisomer.
 3. The cyclohexyl-1,4-diaminecompound of claim 1, wherein said compound is present in the form of amixture of stereoisomers.
 4. The cyclohexyl-1,4-diamine compound ofclaim 1, wherein said compound is present in the form of a racemicmixture.
 5. The cyclohexyl-1,4-diamine compound according to claim 1,wherein R¹ and R² independently of one another represent H; C₁₋₅-alkyl,saturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; or R¹ and R² together form a ring andrepresent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹¹CH₂CH₂ or (CH₂)₃₋₆.
 6. Thecyclohexyl-1,4-diamine compound of claim 1, wherein R¹ and R²independently of one another represent CH₃ or H, where R¹ and R² do notsimultaneously denote H, or R¹ and R² represent CH₂CH₂OCH₂CH₂, (CH₂)₄ or(CH₂)₅.
 7. The cyclohexyl-1,4-diamine compound according to claim 1,wherein R³ represents cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl,anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl,pyrimidyl or pyrazinyl, in each case unsubstituted or mono- orpolysubstituted; C₅₋₆-cycloalkyl, phenyl, naphthyl, anthracenyl,thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl orpyrazinyl bonded via a saturated, unbranched C₁₋₂-alkyl group and ineach case unsubstituted or mono- or polysubstituted.
 8. Thecyclohexyl-1,4-diamine compound according to claim 1, wherein R³represents phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl,indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrimidyl,pyrazinyl or benzothiophenyl, in each case unsubstituted or mono- orpolysubstituted; phenyl, furyl or thiophenyl bonded via a saturated,unbranched C₁₋₂-alkyl group and in each case unsubstituted or mono- orpolysubstituted.
 9. The cyclohexyl-1,4-diamine compound according toclaim 1, wherein R3 represents phenyl, phenethyl, thiophenyl, pyridyl orbenzyl, in each case substituted or unsubstituted, particularlypreferably phenyl, thienyl, 4-chlorobenzyl, benzyl, 3-chlorobenzyl,4-methylbenzyl, 2-chlorobenzyl, 4-fluorobenzyl, 3-methylbenzyl,2-methylbenzyl, 3-fluorobenzyl, 2-fluorobenzyl or phenethyl.
 10. Thecyclohexyl-1,4-diamine compound according to claim 1, wherein R⁴represents C₁₋₅-alkyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl,cyclooctyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl,benzothiophenyl, furanyl, isothiazolyl, imidazolyl, triazolyl,triazinyl, pyrazolyl, benzofuranyl, benzodioxolanyl, isoquinolinyl,phthalazinyl, benzo[1,2,5]thiadiazolyl, benzothiazolyl, benzotriazolyl,quinolinyl, carbazolyl, isoxazolyl, oxazolyl, indolyl, indanyl,benzodioxanyl, indazolyl, benzimidazolyl, pyrrolyl, pyridyl, pyrimidylor pyrazinyl, in each case unsubstituted or mono- or polysubstituted;phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl,furyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, pyrrolyl,pyrimidyl or pyrazinyl bonded via a saturated, unbranched substituted orunsubstituted C₁₋₂-alkyl group and in each case unsubstituted or mono-or polysubstituted.
 11. The cyclohexyl-1,4-diamine compound according toclaim 1, wherein R⁴ represents C₁₋₅-alkyl, branched or unbranched,saturated or unsaturated, cyclohexyl, cyclopentyl, phenyl, benzyl,naphthyl, thiophenyl, benzothiophenyl, furanyl, pyrazolyl, benzofuranyl,isoquinolinyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoxazolyl,oxazolyl, indolyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in eachcase unsubstituted or mono- or polysubstituted, C(O)phenyl, benzyl orphenethyl, in each case unsubstituted or mono- or polysubstituted. 12.The cyclohexyl-1,4-diamine compound according to claim 1, wherein R⁴represents phenyl, C(O)phenyl, C₁₋₅-alkyl, branched or unbranched,saturated or unsaturated, benzyl, pyridyl, pyrimidinyl or indolyl, ineach case unsubstituted or mono- or polysubstituted.
 13. Thecyclohexyl-1,4-diamine compound according to claim 1, wherein Xrepresents (CR⁵R⁶)_(n), phenyl, pyridyl, naphthyl, thiophenyl, furyl,pyrimidinyl or indolyl, in each case unsubstituted or mono- orpolysubstituted and in each case also bridged via a C₁₋₃-alkyl chain,which can be substituted; where n=0, 1, 2, 3 or 4 and R⁵ and R⁶,independently of one another, represent H, C₁₋₅-alkyl, in each casesaturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; phenyl, mono- or polysubstituted orunsubstituted.
 14. The cyclohexyl-1,4-diamine compound according toclaim 1, wherein X represents vinylbenzyl, C₁₋₅-alkyl, branched orunbranched, saturated or unsaturated, phenethyl, phenyl, benzyl orpyridyl, in each case unsubstituted or mono- or polysubstituted.
 15. Thecyclohexyl-1,4-diamine compound according to claim 1, wherein saidcompound is selected from the group consisting of: benzoic acid2-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-benzylester;4-chloro-N-(2-{4-[1-(4-dimethylamino-4-phenyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-benzamide;N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide;acetic acid(4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-phenyl-methylester; benzoic acid2-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzylester; acetic acid[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-phenyl-methylester;N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-phenoxy-benzamide;benzoic acid2-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-benzylester; benzoic acid2-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-benzylester; benzoic acid2-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-benzyl ester; benzoicacid 2-(4-dimethylamino-4-phenyl-cyclohexylcarbamoyl)-benzyl ester;2-(3-chloro-phenoxy)-N-(4-dimethylamino-4-phenyl-cyclohexyl)-acetamide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide;benzoic acid2-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-benzylester; benzoic acid2-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-benzyl ester;benzoic acid2-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-benzylester;2-benzylsulfanyl-N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-acetamide;benzoic acid2-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-benzylester; N-(4-dimethylamino-4-phenyl-cyclohexyl)-4-phenoxy-butyramide;N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-2-phenoxy-acetamide;benzoic acid 2-(4-benzyl-4-pyrrolidin-1-yl-cyclohexylcarbamoyl)-benzylester;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenoxy-acetamide;4-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester; benzoic acid2-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzylester;N-(4-dimethylamino-4-phenyl-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide;5-(2,5-dimethyl-phenoxy)-2,2-dimethyl-pimelic acid[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-amide; benzoic acid2-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-benzylester;4-{1-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-chloro-phenoxy)-2-methyl-propionamide;2-(2-chloro-phenoxy)-N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-methyl-propionamide;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-acetamide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-benzamide;2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-acetamide;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide;2-(3-chloro-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acetamide;2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-benzamide;2-(2-chloro-phenoxy)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-methyl-propionamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide;2-benzyloxy-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide;acetic acid[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylcarbamoyl]-methyl ester;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide;acetic acid[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methylester;2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-acetamide;2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-benzamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide;2-benzyloxy-N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(3-chloro-phenoxy)-acetamide;acetic acid (4-dimethylamino-4-thiophen-2-yl-cyclohexylcarbamoyl)-methylester;2-benzylsulfanyl-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-proplonamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide;benzoic acid 2-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-benzylester;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-butyramide;acetic acid[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide;acetic acid(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-phenyl-methyl ester;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide;2-benzylsulfanyl-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-methoxy-acetamide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenylamino-benzamide;2-benzylsulfanyl-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide;2-benzyloxy-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;2-benzyloxy-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-acetamide;2-benzylsulfanyl-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;4-{1-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-phenoxy-butyramide;2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide;acetic acid (4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-methylester;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-phenoxy-butyramide;4-{1-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-benzamide;benzoic acid2-[2-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-ethyl]-phenylester; acetic acid(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-phenyl-methyl ester;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-phenoxy-butyramide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-methoxy-phenoxy)-5-nitro-benzamide;2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenylamino-benzamide;acetic acid[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester; acetic acid1-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl ester;N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide;N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;acetic acid[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester;2-(3-chloro-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-phenoxy-propionamide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;4-(4-chloro-2-methyl-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-butyramide;acetic acid[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester; N-(4-dimethylamino-4-phenethyl-cyclohexyl)-4-phenoxy-butyramide;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-propionamide;2-phenoxy-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide;4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-butyramide;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-phenoxy-propionamide;2-(4-chloro-phenoxy)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide;acetic acid[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methylester;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-methylsulfanyl-acetamide;acetic acid 1-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-ethylester;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-butyramide;4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-butyramide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;N-(4-dimethylamino-4-phenethyl-cyclohexyl)-2-phenoxy-propionamide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-ethoxy-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide;2-benzyloxy-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;benzoic acid 2-(4-azepan-1-yl-4-benzyl-cyclohexylcarbamoyl)-benzylester;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-phenoxy-acetamide;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-2-phenoxy-propionamide;4-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-butyric acid methylester;2-(4-chloro-phenoxy)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acetamide;acetic acid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester; acetic acid[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester;4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-phenoxy-butyramide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-(2-methoxy-ethoxy)-acetamide;benzoic acid2-{2-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl}-phenylester; benzoic acid2-[2-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]-phenylester;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-phenoxy-nicotinamide;acetic acid[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-phenyl-methylester;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-(4-chloro-2-methyl-phenoxy)-butyramide;N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-2-phenoxy-propionamide;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-phenoxy-acetamide; benzoicacid 2-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-benzyl ester;4-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-butyric acidmethyl ester; benzoic acid2-[2-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl]-phenylester;4-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester; acetic acid1-(4-benzyl-4-dimethylamino-cyclohexylcarbamoyl)-1-methyl-ethyl ester;acetic acid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-phenyl-methylester; benzoic acid2-{2-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}-phenylester; acetic acid1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethylester; N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-phenoxy-acetamide;4-chloro-N-(2-{4-[1-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-benzamide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-isopropylideneaminooxy-propionamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acid ethylester;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-(pyrimidin-2-ylsulfanyl)-acetamide;acetic acid1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethylester; N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acidethyl ester;4-phenoxy-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(4-chloro-phenoxy)-acetamide;acetic acid1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethyl ester;5-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-pimelic acidmethyl ester;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-3-methoxy-propionamide;acetic acid1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethylester;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-phenoxy-butyramide;5-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-pimelic acidmethyl ester;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-methylsulfanyl-acetamide;acetic acid1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethylester; N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-methoxy-acetamide;N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-succinic acid ethyl ester;5-(2,5-dimethyl-phenoxy)-2,2-dimethyl-pimelic acid(4-azepan-1-yl-4-benzyl-cyclohexyl)-amide;N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-phenoxy-propionamide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-methoxy-acetamide;4-(4-chloro-2-methyl-phenoxy)-N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-butyramide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-methylsulfanyl-acetamide;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-phenoxy-butyramide; aceticacid-1-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethylester;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide;N-(2-{4-[1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-4-chloro-benzamide;acetic acid 1-(4-dimethylamino-4-phenethyl-cyclohexylcarbamoyl)-ethylester;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-succinic acid methylester;3-(4-benzyloxy-3-methoxy-phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-acrylamide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(2-methoxy-ethoxy)-acetamide;4-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester;N-(4-benzyl-4-dimethylamino-cyclohexyl)-3-(4-benzyloxy-3-methoxy-phenyl)-acrylamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-2-methoxy-acetamide; acetic acid(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-methyl ester;4-(4-chloro-2-methyl-phenoxy)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-butyramide;N-(4-azepan-1-yl-4-benzyl-cyclohexyl)-2-(4-chloro-phenoxy)-acetamide;2-phenylamino-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-benzamide;N-(2-{4-[1-(4-benzyl-4-pyrrolidin-1-yl-cyclohexylcarbamoyl)-1-methyl-ethoxy]-phenyl}-ethyl)-4-chloro-benzamide;4-chloro-N-[2-(4-{1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;acetic acid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-methyl ester;acetic acid[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-methyl ester;acetic acid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester;acetic acid[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-methyl ester;4-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-butyric acidmethyl ester; acetic acid1-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-ethyl ester;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acrylamide;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acrylamide;acetic acid[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-methyl ester;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acrylamide;N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-2-phenylamino-benzamide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-isopropylideneaminooxy-propionamide;4-chloro-N-(2-{4-[1-methyl-1-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-ethyl)-benzamide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-isopropylideneaminooxy-propionamide;N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-2-(5-trifluoromethyl-pyridin-2-ylsulfanyl)-acetamide;N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-succinic acid methyl ester;benzoic acid 2-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-benzylester; N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-succinic acidmethyl ester;4-chloro-N-(2-{4-[1-methyl-1-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-ethoxy]-phenyl}-ethyl)-benzamide;5-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-pimelic acidmethyl ester; 4-(4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-butyricacid methyl ester; acetic acid1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl ester;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-succinic acid methylester;4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-succinic acid methylester; acetic acid1-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl ester;acetic acid1-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl ester;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-2-phenylamino-benzamide; aceticacid 1-(4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl)-ethyl ester;4-chloro-N-[2-(4-{1-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;4-chloro-N-[2-(4-{1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-1-methyl-ethoxy}-phenyl)-ethyl]-benzamide;acetic acid1-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexylcarbamoyl]-ethyl ester;4-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester;4-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester; N-(4-morpholin-4-yl-4-phenyl-cyclohexyl)-succinic acidmethyl ester; acetic acid1-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-ethyl ester;4-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexylcarbamoyl]-butyric acidmethyl ester;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-acrylamide;benzoic acid2-{2-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexylcarbamoyl]-ethyl}-phenylester; 4-(4-morpholin-4-yl-4-phenyl-cyclohexylcarbamoyl)-butyric acidmethyl ester; acetic acid1-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexylcarbamoyl]-ethyl ester;3-(4-benzyloxy-3-methoxy-phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-acrylamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-ethoxy-acetamide;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acrylamide;3-(4-benzyloxy-3-methoxy-phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acrylamide;2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamidehydrochloride, more polar diastereoisomer;2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamidehydrochloride, less polar diastereoisomer;N-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramidehydrochloride, more polar diastereoisomer; andN-(4-dimethylamino-4-phenylcyclohexyl)-4-phenoxybutyramidehydrochloride, less polar diastereoisomer.
 16. A process for preparing acyclohexyl-1,4-diamine compound according to claim 1, comprising thesteps of: linking a substituted cyclohexane-1,4-diamine with acarboxylic acid corresponding to formula II

by adding coupling reagents or by activating a carboxylic acidcomponent.
 17. The process of claim 16, wherein said process comprisesthe step of preparing an acid chloride.
 18. A pharmaceutical formulationcomprising at least one cyclohexyl-1,4-diamine compound according toclaim 1 and a pharmaceutically acceptable excipient.
 19. A method ofproducing a pharmaceutical formulation comprising the step of combininga pharmaceutically effective amount of a cyclohexyl-1,4-diamine compoundaccording to claim 1 and one or more pharmaceutically acceptableexcipents.
 20. A method of treating pain in a mammal, said methodcomprising administering to said mammal an effective amount of acompound according to claim
 1. 21. The method of claim 20, wherein saidpain is acute, neuropathic or chronic pain.
 22. A method of treating acondition selected from the group consisting of anxiety states, stressand stress-associated syndromes, depression, epilepsy, Alzheimer'sdisease, senile dementia, catalepsy, general cognitive dysfunctions,learning and memory disorders, withdrawal symptoms, alcohol abuse ordependency, drug abuse or dependency, medicament abuse or dependency,sexual disfunction, cardiovascular disease, hypotension, hypertension,tinnitus, pruritus, migraine, impaired hearing, deficient intestinalmotility, impaired food intake, anorexia, obesity, locomotor disorders,diarrhea, cachexia, urinary incontinence or providing a muscle relaxant,nootropic, anticonvulsive or anaesthetic or for co-administration withan opioid analgesic or with an anaesthetic, for diuresis orantinatriuresis, anxiolysis, for modulation of movement activity, formodulation of neurotransmitter secretion and treatment ofneurodegenerative diseases associated therewith, for the treatment ofwithdrawal symptoms or for reducing the addiction potential of opioids,said method comprising administering to a subject in need thereof apharmaceutically effective amount of a compound according to claim 1.23. A cyclohexyl-1,4-diamine compound corresponding to formula I

wherein R¹ and R², independently of one another, represent H;C₁₋₅-alkyl, in each case saturated or unsaturated, branched orunbranched, mono- or polysubstituted or unsubstituted; C₃₋₈-cycloalkyl,in each case mono- or polysubstituted or unsubstituted; or aryl,C₃₋₈-cycloalkyl or heteroaryl bonded via C₁₋₃-alkyl and in each casemono- or polysubstituted or unsubstituted; or R¹ and R² together form aring and represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆, whereinR¹⁰ denotes H; C₁₋₅-alkyl, in each case saturated or unsaturated,branched or unbranched, mono- or polysubstituted or unsubstituted;C_(3,8)-cycloalkyl, in each case mono- or polysubstituted orunsubstituted; aryl or heteroaryl, in each case mono- or polysubstitutedor unsubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl bonded viaC₁₋₃-alkyl and in each case mono- or polysubstituted or unsubstituted;C(O)phenyl, C(O)heteroaryl, C(O)C₁₋₅-alkyl, in each case substituted orunsubstituted; R³ represents C₁₋₅-alkyl, in each case saturated orunsaturated, branched or unbranched, mono- or polysubstituted orunsubstituted; C₃₋₈-cycloalkyl, in each case mono- or polysubstituted orunsubstituted; aryl or heteroaryl, in each case unsubstituted or mono-or polysubstituted; aryl, heteroaryl or C₃₋₈-cycloalkyl bonded viaC₁₋₃-alkyl and in each case unsubstituted or mono- or polysubstituted; Xrepresents (CR⁵R⁶)_(n); aryl or heteroaryl, in each case unsubstitutedor mono- or polysubstituted and in each case also bridged via aC₁₋₃-alkyl chain, which may be substituted; where n=0, 1, 2, 3, or 4; Arepresents NH, ON, wherein the bond between N and R⁴ is a double bond, Oor S, l represents 1 or 2; R⁴ represents C₁₋₅-alkyl, in each casesaturated or unsaturated, branched or unbranched, mono- orpolysubstituted or unsubstituted; C₃₋₈-cycloalkyl, in each case mono- orpolysubstituted or unsubstituted; aryl or heteroaryl, in each case mono-or polysubstituted or unsubstituted; or aryl, C₃₋₈-cycloalkyl orheteroaryl bonded via C₁₋₃-alkyl and in each case mono- orpolysubstituted or unsubstituted; R⁵ and R⁶ independently of one anotherrepresent H, C₁₋₅-alkyl, in each case saturated or unsaturated, branchedor unbranched, mono- or polysubstituted or unsubstituted; aryl, in eachcase mono- or polysubstituted or unsubstituted, provided if l represents1 and A represents O or S, then X is not heteroaryl; or an acid, base,solvate or physiologically acceptable salt thereof.
 24. Thecyclohexyl-1,4-diamine compound of claim 1, wherein said compound ispresent in the form of a hydrate.